The Food and Drug Administration’s Oncologic Drugs Advisory Committee voted against approving a new drug application for quizartinib for adult patients with relapsed/refractory FLT3-ITD–positive AML.
The Food and Drug Administration (FDA)’s Oncologic Drugs Advisory Committee (ODAC) voted 8 to 3 against approving a new drug application for quizartinib for adult patients with relapsed/refractory FLT3-ITD—positive acute myeloid leukemia (AML).
With this, the FDA will now make a decision on the quizartinib indication by Aug. 25, 2019.
The FLT3 inhibitor’s new drug application was based on findings from the phase 3 QuANTUM-R study, in which quizartinib reduced the risk of death by 24% compared with salvage chemotherapy in patients with FLT3-ITD—positive relapsed/refractory AML after first-line treatment with or without hematopoietic stem cell transplantation (HSCT). At a median follow-up of 23.5 months, the median overall survival was 6.2 months with quizartinib, compared with 4.7 months with salvage chemotherapy.
Prior to the ODAC meeting, the FDA conducted its own efficacy analysis, and determined the median overall survival was 26.9 weeks with quizartinib compared with 20.4 weeks with chemotherapy.
The phase 3 trial also showed that the median event-free survival was 1.4 months with quizartinib versus 0.9 months with salvage chemotherapy. Meanwhile, the internal FDA analysis also did not demonstrate a significant event-free survival benefit with quizartinib versus chemotherapy (6.0 vs. 3.7 weeks).
In addition, the trial data showed that the overall response rate was 69% with quizartinib versus 30% with salvage chemotherapy. The composite complete remission rate was 48% versus 27% and the partial response rate was 21% versus 3%, respectively. The median duration of composite complete remission was 12.1 weeks versus 5.0 weeks, respectively.
Although this analysis confirmed a benefit with quizartinib, the FDA explained in its ODAC briefing document that it found issues in its review raising concerns over the “credibility” and “generalizability” of the trial data.
“I voted no based on the data available. The efficacy results that we were shown are a modest six weeks. And if I felt confident in those data, that would have been enough for me in the setting of AML, but a lot of the questions that were raised with respect to bias, confounding, and I do think the issue of equipoise is a real one in the setting of this particular study—it raises questions about whether or not that survival benefit is real,” said Dr. Heidi D. Klepin, associate professor of internal medicine in the section of hematology and oncology at Wake Forest University Health Sciences.
Moreover, the FDA’s internal safety analysis of the QuANTUM-R study was mostly consistent with the safety findings included in the new drug application, which listed the most common treatment-emergent side effects as nausea, anemia, electrocardiogram QT prolonged, thrombocytopenia, pyrexia, hypokalemia, febrile neutropenia, vomiting, fatigue, diarrhea, neutropenia, white blood cell count decreased, platelet count decreased, neutrophil count decreased, headache and decreased appetite.
The application also listed side effects of special interest, including infection (77%), hemorrhage (49%), hepatic disorders (32%), QT prolongation (31%), cardiac arrhythmias (12%) and cardiac failure (2%).
In its ODAC briefing document, the FDA focused on cardiac toxicity as a key concern with quizartinib, noting the risk of cardiac side effects was substantially higher with quizartinib versus chemotherapy. Additional safety issues identified in the FDA safety analysis included potentially fatal differentiation syndrome, acute febrile neutrophilic dermatosis and prolonged cytopenias.
“In the realm of hematology/oncology, there are no patients sicker than acute leukemia patients, and no physicians more intensely watching the details than leukemia doctors, and so I’m not particularly worried that this cardiac safety question will somehow fall through the cracks,” said Dr. Philip C. Hoffman, professor of medicine at The University of Chicago Section of Hematology/Oncology in the Department of Medicine.
“I agree with some of the others, that I don’t get the sense that, at least based on the data right now, that this is a blockbuster (drug), but it does seem like it’s one more agent in the armamentarium that can be useful in leukemia patients, perhaps as a way to get patients in sufficient remission to move toward a transplant,” he added.
This article was adapted from an article that originally appeared on OncLive as “FDA Panel Votes Against Quizartinib Approval for AML.”